Tiacumicin compounds are naturally occurring compounds with an antibiotic activity that can be obtained by cultivating various microorganisms belonging to the Actinoplanes family (especially the genus Dactylosporangium aurantiacum, subspecies hamdenensis) in a suitable nutrient medium at a suitable temperature and isolating the compounds having antibiotic activity against a variety of microorganisms (tiacumicins A-F; U.S. Pat. No. 4,918,174). Especially tiacumicins B and C turned out to possess antibiotic activity against a number of Gram-positive bacteria in vitro including strains resistant to therapeutic antibiotics, used at the time. U.S. Pat. No. 5,583,115 discloses dialkyltiacumicin compounds, which are derivatives of the above-mentioned tiacumicin compounds A-F, were found to have in vitro activity against a variety of bacterial pathogens and in particular against Clostridium species. U.S. Pat. No. 5,767,096 discloses bromotiacumicin compounds, which are also derivatives of tiacumicin compounds A-F, which were found to have in vitro activity against some bacterial pathogens and in particular against Clostridium species.
From a chemical point of view the tiacumicins share an 18-membered macrocyclic ring, which is glycosidically attached to one or two optionally substituted sugar molecules (U.S. Pat. No. 4,918,174 and WO 2004/014295) as follows:

WO 2004/014295 describes substantially pure R-tiacumicins, obtained by submerged aerobic fermentation of Dactylosporangium aurantiacum hamdenensis. WO 2006/085838 discloses pharmaceutical compositions containing R-tiacumicins and especially R-tiacumicin B, which contains an R-hydroxyl-group at C19, which shows surprisingly lower MIC values when tested in vitro against Clostridium species than the optically pure S-isomer of tiacumicin B and other tiacumicin related compounds.
Chinese patent applications having publication numbers 102030791 and 102219815 respectively and S. Niu et al. (2011) in ChemBioChem 12: page 1740-1748 describe 11 new tiacumicin analogues all lacking the 2′-O-methyl group on the internal rhamnose moiety. Two of those analogues have shown to have improved antibacterial properties.
R-tiacumicin B is also known under the name fidaxomicin (3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]methyl]-12(R)-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaen-2-one or oxacyclooctadeca-3,5,9,13,15-pentaen-2-one, 3-[[[6-deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl]oxy]methyl]-12-[[6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl]oxy]-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-, (3E,5E,8S,9E,11S,12R,13E,15E,18S)). It is a compound that has a narrow antimicrobial spectrum, with activity against Clostridium difficile and most strains of staphylococci and enterococci but negligible activity against gram-negative organisms and fungi. It is obtained by fermentation of Dactylosporangium aurantiacum and corresponds to the following formula (II):

According to an in vitro BCS (Biopharmaceutics Classification System) study, fidaxomicin is a BCS Class IV compound (low solubility, low permeability). Upon oral administration fidaxomicin is poorly absorbed from the intestinal tract and is therefore associated with a low incidence of systemic side effects. Fidaxomicin is indicated for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated disease (CDAD) and prevention of recurrences. Along with its narrow antimicrobial spectrum, fidaxomicin also has a prolonged post antibiotic effect against C. difficile. Besides the obvious benefit to the patient, the prevention of recurrence would eliminate the costs of treating additional episodes of C. difficile infection and should reduce the rate of person-to-person transmission. The recommended dose for adults and elderly people (65 years and older) is 200 mg administered twice daily (q12 h) for 10 days.
Tablets containing 200 mg fidaxomicin are commercially available in Europe (under the trademark Dificlir) and in the USA (under the trademark Dificin). WO 2008/091518 discloses pharmaceutical compositions of tiacumicins, and especially fidaxomicin. In example 1 a tablet formulation is disclosed, which contains 200 mg fidaxomicin in admixture with microcrystalline cellulose, starch, hydroxypropylcellulose, butylated hydroxytoluene, sodium starch glycolate and magnesium stearate. According to example 2 the addition of an anti-oxidant, such as butylhydroxytoluene or butylhydroxyanisole is required in order to prevent the formation of degradation products of fidaxomicin, such as related compound L, which is believed to be an oxidation product of fidaxomicin.
According to the Summary of Product Characteristics the marketed product in Europe is an immediate release tablet, containing microcrystalline cellulose, pregelatinised starch, hydroxypropyl cellulose, butylated hydroxytoluene, sodium starch glycolate and magnesium stearate as the excipients; the tablet is provided with a film-coating, containing polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol and soy lecithin. Adult sick people may experience difficulties when swallowing the tablet.
On the other hand the tablet is not indicated for children. Nowadays Health Authorities require conducting clinical trials in paediatric patient populations with dosage forms that have been specifically developed for these target populations. There are various possibilities for such paediatric dosage forms such as small tablets, dispersible tablets, granulates, powders and granulates for suspension. However, liquid formulations (as such or to be prepared shortly before administration) normally are the formulations of choice for administration to the whole paediatric patient population from birth up till and including childhood. It goes without saying that liquid formulations may also be useful for administration to adult patients, who have difficulties in swallowing tablet formulations.
EP-1652524A1 disclosed in example 1 a dry syrup preparation comprising loratadine as the active ingredient in admixture with hydroxypropylcellulose and a sugar compound. When water was added to form an aqueous suspension, no foaming was observed. The same preparation without hydroxypropylcellulose could not prevent the foaming property.
WO 2005/009474 discloses a dry syrup formulation, comprising a hardly water soluble drug and a specified amount of a hydroxypropyl cellulose with a specified viscosity in water, which formulation after adding water is converted into a uniform dispersion without hardly forming any foam. The formulation may further contain one or more sugars.
US 2006/269485 aimed at seeking a solution for the problem that the addition of an active ingredient to a foam emulsion composition, may destabilise the foam and provides aerosol packages comprising an antibiotic foamable composition, including at least one organic carrier, a surface active agent, at least one polymeric additive such as a gelling agent, water and a gas propellant. Optionally the composition contains a foam adjuvant.
WO 2008/091554 discloses polymorphs of tiacumicin and the preparation thereof. The polymorphs were characterised by X-ray diffraction diagram, melting point and DSC (Differential Scanning calorimetry)-plots, but no further properties were mentioned.
Xanthan gum is an anionic polysaccharide produced by the bacterium Xanthomonas campestris. Its structure is composed of a β-(1-4)-D-glucose main chain and side chains each one out of two glucose residues. Side chains are constituted of an α-D-mannose, β-D-glucuronic acid and β-D-mannose as terminal residues. In water, the stiff polymer chain may exist as a single, double or triple helix that interacts with another chain to form a complex, loosely bound network. This particular structure gives the gum its unusual thickening properties, with a yield stress, shear-thinning and thixotropic behaviours. In the pharmaceutical field xanthan gum is used as a suspending, stabilising and thickening agent in oral and topical formulations, for the production of sustained-release matrix tablets or for its muco-adhesive properties (Handbook of pharmaceutical excipients, 6th ed.). Several different grades are commercially available (Keltrol, Keltrol 360, Xantural).
Carrageenan according to USP32-NF27 is a hydrocolloid obtained by extraction with water or aqueous alkali from some members of the class Rhodophyceae (red seaweed). It consists mainly of potassium, sodium, calcium, magnesium and ammonium sulfate esters of galactose and 3,6-anhydrogalactose copolymers. These hexoses are alternately linked at the alpha-1,3 and beta-1,4 sites in the polymer. The carrageenans are divided into 3 families according to the position of the sulphate groups and the presence or absence of anhydrogalactose. Lambda-carrageenan is a non gelling polymer containing about 35% ester sulphate by weight and no 3,6-anhydrogalactose. Iota-carrageenan is a gelling polymer containing about 32% ester sulphate by weight and approximately 30% 3,6-anhydrogalactose. Kappa-carrageenan is a strongly gelling polymer containing about 32% ester sulphate by weight and approximately 30% 3,6-anhydrogalactose. The carrageenans have been used in a variety of non parenteral pharmaceutical dosage-forms, including suspensions (wet and reconstitutable), emulsions, gels, creams and lotions as an emulsifying agent, gel base, stabilising agent, suspending agent, sustained-release agent, viscosity increasing agent. In suspension formulations usually the lambda and the iota carrageenan fractions are used.
Guar gum consists of linear chains of (1→4)-beta-D-mannpyranosyl units with alpha-D-galactopyranosyl units attached by (1→6) linkages. The ration of D-galactose to D-mannose is between 1:1.4 and 1:2. It is used as a suspending agent, tablet binder, tablet disintegrant and viscosity increasing agent. Guar gum is a galactomannan, commonly used in cosmetics, food products and pharmaceutical formulations. In oral and topical products guar gum is used as a suspending, thickening and stabilising agent. The USP32-NF27 describes guar gum as a gum obtained from the ground endosperms of Cyamopsis tetragonulobus. It consists mainly of a high molecular weight hydrocolloidal polysaccharide, composed of galactan and mannan units combined through glycoside linkages, which may be described chemically as a galactomannan. The main components are polysaccharides composed of D-galactose and D-mannose in molecular ratios of 1:1.4 to 1:2. The molecule consists of a linear chain of beta-(1-4)-glycosidically linked mannopyranoses and single alpha-(1-6)-glycosidically linked galactopyranoses.
Sodium alginate consists mainly of the sodium salt of alginic acid, which is a mixture of polyuronic acids composed of residues of D-mannuronic acid and L-guluronic acid. Sodium alginate is used in a variety of oral and topical pharmaceutical formulations as a stabilising agent, a suspending agent, a disintegrant, a tablet binder and a viscosity increasing agent.
Water dispersible cellulose, also known as “microcrystalline cellulose and carboxymethyl cellulose sodium”, e.g. in the U.S. Pharmacopoeia/National Formulary, is used to produce thixotropic gels suitable as suspending vehicles in pharmaceutical and cosmetic formulations. The sodium carboxymethylcellulose aids dispersion and serves as a protective colloid. The water dispersible celluloses are colloidal forms of microcrystalline cellulose, prepared by chemical depolymerisation of highly purified wood pulp, the original crystalline areas of the fibres being combined with sodium carboxymethyl cellulose and spray-dried. These also find wide use as a pharmaceutical and cosmetic excipient, namely as an oil-in-water emulsifier, an emulsion or foam stabilising agent, as a suspending agent in pharmaceutical suspensions (readymade as well as reconstitutable suspension) and as a thickening agent. Four types of the said celluloses have been marketed under trade names as Avicel® RC-501 (containing 7.1-11.9% of sodium carboxylmethyl cellulose), Avicel® RC-581 (containing 8.3-13.8% of sodium carboxymethyl cellulose), Avicel® RC-591 (containing 8.3-13.8% of sodium carboxymethyl cellulose) and Avicel® CL-611 (containing 11.3-18.8% of sodium carboxymethyl cellulose). All types are hygroscopic powders, which are insoluble in organic solvents and dilute acids, and partially soluble in both dilute alkali and water (due to the sodium carboxymethyl cellulose component). Similar products have been marketed under the trade name Ceolus®.
Acacia gum or gum arabic is a complex, loose aggregate of sugars and hemicelluloses with a molecular weight of approx. 240,000-580,000. The aggregate consists essentially of an arabic acid nucleus to which are connected calcium, magnesium and potassium along with the sugars arabinose, galactose and rhamnose. Acacia is mainly used in oral and topical pharmaceutical formulations as a suspending and emulsifying agent.
In order to enable accurate dosing of fidaxomicin to paediatric patients and to make the product available to the adult patient population with swallowing problems, there is a need for developing an alternative, easy to administer and stable dosage-form comprising fidaxomicin.